Balancing immunity and tolerance: genetic footprint of natural selection in the transcriptional regulatory region of HLA-G

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Síntese estendida: uma investigação histórico-filosófica

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Stone tool use by adult wild bearded capuchin monkeys (Cebus libidinosus). Frequency, efficiency and tool selectivity

Chimpanzees have been the traditional referential models for investigating human evolution and stone tool use by hominins. We enlarge this comparative scenario by describing normative use of hammer stones and anvils in two wild groups of bearded capuchin monkeys (Cebus libidinosus) over one year. We found that most of the individuals habitually use stones and anvils to crack nuts and other encased food items. Further, we found that in adults (1) males use stone tools more frequently than females, (2) males crack high resistance nuts more frequently than females, (3) efficiency at opening a food by percussive tool use varies according to the resistance of the encased food, (4) heavier individuals are more efficient at cracking high resistant nuts than smaller individuals, and (5) to crack open encased foods, both sexes select hammer stones on the basis of material and weight. These findings confirm and extend previous experimental evidence concerning tool selectivity in wild capuchin monkeys (Visalberghi et al., 2009b; Fragaszy et al., 2010b). Male capuchins use tools more frequently than females and body mass is the best predictor of efficiency, but the sexes do not differ in terms of efficiency. We argue that the contrasting pattern of sex differences in capuchins compared with chimpanzees, in which females use tools more frequently and more skillfully than males, may have arisen from the degree of sexual dimorphism in body size of the two species, which is larger in capuchins than in chimpanzees. Our findings show the importance of taking sex and body mass into account as separate variables to assess their role in tool use. (C) 2011 Elsevier Ltd. All rights reserved.

Rag2-/-;gammac-/- immunodeficient mice, a new preclinical model to study antitumor approaches

Animal models have been relevant to study the molecular mechanisms of cancer and to develop new antitumor agents. Anyway, the huge divergence in mouse and human evolution made difficult the translation of the gained achievements in preclinical mouse based studies. The generation of clinically relevant murine models requires their humanization both concerning the creation of transgenic models and the generation of humanized mice in which to engraft a functional human immune system, and reproduce the physiological effects and molecular mechanisms of growth and metastasization of human tumors. In particular, the availability of genotypically stable immunodepressed mice able to accept tumor injection and allow human tumor growth and metastasization would be important to develop anti-tumor and anti-metastatic strategies. Recently, Rag2-/-;gammac-/- mice, double knockout for genes involved in lymphocyte differentiation, had been developed (CIEA, Central Institute for Experimental Animals, Kawasaki, Japan). Studies of human sarcoma metastasization in Rag2-/-; gammac-/- mice (lacking B, T and NK functionality) revealed their high metastatic efficiency and allowed the expression of human metastatic phenotypes not detectable in the conventionally used nude murine model. In vitro analysis to investigate the molecular mechanisms involved in the specific pattern of human sarcomas metastasization revealed the importance of liver-produced growth and motility factors, in particular the insulin-like growth factors (IGFs). The involvement of this growth factor was then demonstrated in vivo through inhibition of IGF signalling pathway. Due to the high growth and metastatic propensity of tumor cells, Rag2-/-;gammac-/- mice were used as model to investigate the metastatic behavior of rhabdomyosarcoma cells engineered to improve the differentiation. It has been recently shown that this immunodeficient model can be reconstituted with a human immune system through the injection of human cord blood progenitor cells. The work illustrated in this thesis revealed that the injection of different human progenitor cells (CD34+ or CD133+) showed peculiar engraftment and differentiation abilities. Experiments of cell vaccination were performed to investigate the functionality of the engrafted human immune system and the induction of specific human immune responses. Results from such experiments will allow to collect informations about human immune responses activated during cell vaccination and to define the best reconstitution and experimental conditions to create a humanized model in which to study, in a preclinical setting, immunological antitumor strategies.

The Savannah hypotheses: origin, reception and impact on paleoanthropology

The reconstruction of the human past is a complex task characterized by a high level of interdisciplinarity. How do scientists from different fields reach consensus on crucial aspects of paleoanthropological research? The present paper explores this question through an historical analysis of the origin, development, and reception of the savannah hypotheses (SHs). We show that this model neglected to investigate crucial biological aspects which appeared to be irrelevant in scenarios depicting early hominins evolving in arid or semi-arid open plains. For instance, the exploitation of aquatic food resources and other aspects of hominin interaction with water were largely ignored in classical paleoanthropology. These topics became central to alternative ideas on human evolution known as aquatic hypotheses. Since the aquatic model is commonly regarded as highly controversial, its rejection led to a stigmatization of the whole spectrum of topics around water use in non-human hominoids and hominins. We argue that this bias represents a serious hindrance to a comprehensive reconstruction of the human past. Progress in this field depends on clear differentiation between hypotheses proposed to contextualize early hominin evolution in specific environmental settings and research topics which demand the investigation of all relevant facets of early hominins' interaction with complex landscapes.

Genomic Data Reveal a Complex Making of Humans

In the last few years, two paradigms underlying human evolution have crumbled. Modern humans have not totally replaced previous hominins without any admixture, and the expected signatures of adaptations to new environments are surprisingly lacking at the genomic level. Here we review current evidence about archaic admixture and lack of strong selective sweeps in humans. We underline the need to properly model differential admixture in various populations to correctly reconstruct past demography. We also stress the importance of taking into account the spatial dimension of human evolution, which proceeded by a series of range expansions that could have promoted both the introgression of archaic genes and background selection.

Population genetics of VNTR loci and their applications in evolutionary studies

Variable number of tandem repeats (VNTR) are genetic loci at which short sequence motifs are found repeated different numbers of times among chromosomes. To explore the potential utility of VNTR loci in evolutionary studies, I have conducted a series of studies to address the following questions: (1) What are the population genetic properties of these loci? (2) What are the mutational mechanisms of repeat number change at these loci? (3) Can DNA profiles be used to measure the relatedness between a pair of individuals? (4) Can DNA fingerprint be used to measure the relatedness between populations in evolutionary studies? (5) Can microsatellite and short tandem repeat (STR) loci which mutate stepwisely be used in evolutionary analyses?^ A large number of VNTR loci typed in many populations were studied by means of statistical methods developed recently. The results of this work indicate that there is no significant departure from Hardy-Weinberg expectation (HWE) at VNTR loci in most of the human populations examined, and the departure from HWE in some VNTR loci are not solely caused by the presence of population sub-structure.^ A statistical procedure is developed to investigate the mutational mechanisms of VNTR loci by studying the allele frequency distributions of these loci. Comparisons of frequency distribution data on several hundreds VNTR loci with the predictions of two mutation models demonstrated that there are differences among VNTR loci grouped by repeat unit sizes.^ By extending the ITO method, I derived the distribution of the number of shared bands between individuals with any kinship relationship. A maximum likelihood estimation procedure is proposed to estimate the relatedness between individuals from the observed number of shared bands between them.^ It was believed that classical measures of genetic distance are not applicable to analysis of DNA fingerprints which reveal many minisatellite loci simultaneously in the genome, because the information regarding underlying alleles and loci is not available. I proposed a new measure of genetic distance based on band sharing between individuals that is applicable to DNA fingerprint data.^ To address the concern that microsatellite and STR loci may not be useful for evolutionary studies because of the convergent nature of their mutation mechanisms, by a theoretical study as well as by computer simulation, I conclude that the possible bias caused by the convergent mutations can be corrected, and a novel measure of genetic distance that makes the correction is suggested. In summary, I conclude that hypervariable VNTR loci are useful in evolutionary studies of closely related populations or species, especially in the study of human evolution and the history of geographic dispersal of Homo sapiens. (Abstract shortened by UMI.) ^

Age determination and color reflectance of ODP Hole 165-1002D

Attempts to place Palaeolithic finds within a precise climatic framework are complicated by both uncertainty over the radiocarbon calibration beyond about 21,500 14C years bp (Reimer et al., 2004) and the absence of a master calendar chronology for climate events from reference archives such as Greenland ice cores or speleothems (Svensson et al., 2006, doi:10.1016/j.quascirev.2006.08.003). Here we present an alternative approach, in which 14C dates of interest are mapped directly onto the palaeoclimate record of the Cariaco Basin by means of its 14C series (Hughen et al., 2004, doi:10.1126/science.1090300), circumventing calendar age model and correlation uncertainties, and placing dated events in the millennial-scale climate context of the last glacial period. This is applied to different sets of dates from levels with Mousterian artefacts, presumably produced by late Neanderthals, from Gorham's Cave in Gibraltar: first, generally accepted estimates of about 32,000 14C years bp for the uppermost Mousterian levels (Pettitt and Bailey, 2000; Bronk Ramsey et al., 2002, doi:10.1111/1475-4754.00040); second, a possible extended Middle Palaeolithic occupation until about 28,000 14C years bp (Finlayson et al., 2006, doi:10.1038/nature05195); and third, more contentious evidence for persistence until about 24,000 14C years bp (Finlayson et al., 2006, doi:10.1038/nature05195). This study shows that the three sets translate to different scenarios on the role of climate in Neanderthal extinction. The first two correspond to intervals of general climatic instability between stadials and interstadials that characterized most of the Middle Pleniglacial and are not coeval with Heinrich Events. In contrast, if accepted, the youngest date indicates that late Neanderthals may have persisted up to the onset of a major environmental shift, which included an expansion in global ice volume and an increased latitudinal temperature gradient. More generally, our radiocarbon climatostratigraphic approach can be applied to any 'snapshot' date from discontinuous records in a variety of deposits and can become a powerful tool in evaluating the climatic signature of critical intervals in Late Pleistocene human evolution.

O DINHEIRO E O SAGRADO Uma leitura das interfaces de fenômenos culturais, religiosos e econômicos e de seus reflexos existenciais, à luz das Ciências Sociais e da Psicologia Analítica

Esta tese é o resultado de uma pesquisa sobre o uso e a influência do dinheiro no que tange às questões existenciais, no contexto capitalista, ligadas ao trinômio: saúde, amor e espiritualidade. Para isso, foram analisados vários tipos de vínculo, afetivos ou não, existentes nas relações humanas, no âmbito da família, do mercado e do Estado, convergindo para a busca do sagrado que dá sentido e significado existenciais. O eixo teórico se localiza em uma interface entre as Ciências Sociais e a Psicologia Analítica, de Carl Gustav Jung (1875-1961), que expressa em sua obra a necessidade humana de encontrar a realização do ser pela conquista consciente de um estado de integração evolutiva. Esta dimensão integral existe quando é realizada a unificação dos vários aspectos do eu com o inconsciente, expressos teleologicamente no processo de individuação. O resultado da evolução científica e tecnológica, acrescido pela supremacia do mercado, abrange praticamente todas as esferas da vida humana, imprimindo uma importância excessiva ao dinheiro. Por exemplo, até o campo religioso foi invadido pela lógica monetária, que se instalou impondo uma atitude monetarizada nas práticas e ritos religiosos, como ocorre em algumas igrejas neopentecostais. Por sua vez, a supervalorização do dinheiro contribui para um processo que combina dessacralização e exclusão social, bem como para o aumento significativo de doenças em todas as instâncias em que as trocas deixaram de acontecer livremente. Com a interdição das trocas, a vida se esvai, comprometendo a evolução humana nas instâncias físicas, psíquicas, sociais, espirituais, familiares, afetivas ou profissionais. Como os desejos de lucro e de acúmulo impedem as trocas, a conquista da dimensão integral vai ficando sombreada até ser substituída pela anestesia do consumo, no sentido de aliviar, apesar de não eliminar, os sentimentos de angústia pela falta de sentido existencial. Busca-se neste trabalho o entendimento da razão pela qual o ser humano contemporâneo deixou de trocar livremente e passou a acumular, muitas vezes por meio de consumo do supérfluo, ficando à mercê de um mercado que pretende ser hegemônico, colocando inclusive o dinheiro como caminho de cura e salvação. Fizemos um levantamento das possibilidades que podem restar para a concretização de uma readequação do uso do dinheiro a serviço da individuação e da realização existencial.(AU)

O DINHEIRO E O SAGRADO Uma leitura das interfaces de fenômenos culturais, religiosos e econômicos e de seus reflexos existenciais, à luz das Ciências Sociais e da Psicologia Analítica

Esta tese é o resultado de uma pesquisa sobre o uso e a influência do dinheiro no que tange às questões existenciais, no contexto capitalista, ligadas ao trinômio: saúde, amor e espiritualidade. Para isso, foram analisados vários tipos de vínculo, afetivos ou não, existentes nas relações humanas, no âmbito da família, do mercado e do Estado, convergindo para a busca do sagrado que dá sentido e significado existenciais. O eixo teórico se localiza em uma interface entre as Ciências Sociais e a Psicologia Analítica, de Carl Gustav Jung (1875-1961), que expressa em sua obra a necessidade humana de encontrar a realização do ser pela conquista consciente de um estado de integração evolutiva. Esta dimensão integral existe quando é realizada a unificação dos vários aspectos do eu com o inconsciente, expressos teleologicamente no processo de individuação. O resultado da evolução científica e tecnológica, acrescido pela supremacia do mercado, abrange praticamente todas as esferas da vida humana, imprimindo uma importância excessiva ao dinheiro. Por exemplo, até o campo religioso foi invadido pela lógica monetária, que se instalou impondo uma atitude monetarizada nas práticas e ritos religiosos, como ocorre em algumas igrejas neopentecostais. Por sua vez, a supervalorização do dinheiro contribui para um processo que combina dessacralização e exclusão social, bem como para o aumento significativo de doenças em todas as instâncias em que as trocas deixaram de acontecer livremente. Com a interdição das trocas, a vida se esvai, comprometendo a evolução humana nas instâncias físicas, psíquicas, sociais, espirituais, familiares, afetivas ou profissionais. Como os desejos de lucro e de acúmulo impedem as trocas, a conquista da dimensão integral vai ficando sombreada até ser substituída pela anestesia do consumo, no sentido de aliviar, apesar de não eliminar, os sentimentos de angústia pela falta de sentido existencial. Busca-se neste trabalho o entendimento da razão pela qual o ser humano contemporâneo deixou de trocar livremente e passou a acumular, muitas vezes por meio de consumo do supérfluo, ficando à mercê de um mercado que pretende ser hegemônico, colocando inclusive o dinheiro como caminho de cura e salvação. Fizemos um levantamento das possibilidades que podem restar para a concretização de uma readequação do uso do dinheiro a serviço da individuação e da realização existencial.(AU)